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J o w l OfNatural P&s Vol. 48, No. 1 , p p . 142-143, Jan-Feb 1985
ABSOLUTE CONFIGURATION OF DEGLUCOPTEROCEREINE: CONVERSION INTO R-( +)-N-METHYLCALYCOTOMINE P. KEREKES,' PADM N .
sHARMA,3
A. BROSSI,
Medicinal Chemistry Sertion, Labmatoiy of Chemistry, National Institute of Arthritis, Diabeta and Digativc and Kidney Diseuses, National lnstitutes of Health, Bethaah, Maryland 20205 and J.L. M C ~ U G H L I N Department of Medicinal Chemistry and Pharmacognosy, Schwl of Pharmacy and Pharmacal Scienca, Purdue Uniwsity, West Lafayette, lndiana 47907
Pterocereine (l),a glucotetrahydroisoquinoline alkaloid from the cactus Pterocereus gaumwi (Br. & R.) MacDoug. & Mir., afforded by hydrolysis deglucopterocereine (2) of unknown absolute configuration (1). Phenolic deoxygenation (2) of 2 by reductive cleavage of its phenyltetrazolyl ether derivative (3)has afforded R-( )-N-methylcalycotomine (4).Identity of 4 with material prepared from R-(+)-calycotomine ( 5 ) (3) by reductive N-methylation (4) was established by tlc and a comparison of mass and cd-spectra of 4 obtained from 2 and 5 . Thus, the R-configuration of deglucopterocereine (2) was established. Furthermore, optical characterization can be carried out by cd spectroscopy with only small amounts ( 1mg or less) of materials (5).
+
R2
EXPERIMENTAL GENERALEXPERIMENTAL PROCEDURES.Ir spectra were recorded with a Beckman 4230 instrument. Nmr spectra were obtained in CDCI, with a Varian HR-220 spectrometer with TMS as an internal standard. Cims spectra were obtained by using a Finnigan 1015 D spectrometer. Cdspectra were measured in MeOH solution at 283 nm with a J-5OOA spectropolarimeter (@=molecular rotation). TICwas carried out on silica gel plates, purchased from Analtech, Inc., developed with CHC13-MeOH-NH40H (94:5:1). CONVERSIONOF
DEGLUCOITEROCEREINE
(1)INTO (+)-N-METHYCALYCOTOMINE (2).A mixture of 1 hydrochloride (20 mg), 5-chlorc1-phenyl-1H-tetrazole (14.5 mg), and K,CO, (38.7 mg) in Me,CO (20 ml) was refluxed for 24 h. Evaporation to dryness, addition of H,O (20 ml) and a few drops of 10% NH40H afforded, after extraction with CHCI, (3 X 20 ml) and usual workup, 20 mg of an oily residue. Column chromatography on silica gel (CHC1,-MeOH",OH, 90: 10: 1) gave 8.5 mg of the amorphous tetrazolyl ether 3: cims m/z 398 (M+ 1). Hydrogenation of 3 (8.0 rng) in EtOH (10 ml) over 10%Pd/C-catalyst (10 mg) at 50" and 48 psi for 14 h afforded, after usual workup, 2.1 mg of an oil: cims m/z 238 (M+ + l ) , 206 (M+ -CH,OH); Cd @ ( h nm)=-30.2I0 (283). Identical by tlc with (+)-N-methycalycotomine
+
(4). (+)-N-METHYCALYCOTOMINE (4)FROM (+)(5).-(+)-Calycotomine (1 11 mg), ( ~ ] ~ ' ~ = + 2 3("c = l , MeOH) [lit. (2) [ ~ x ] ~ ~ D = + 2(c=O.5, 4' MeOH)], prepared from its tartrate salt was dissolved in MeOH (0.5 ml), and 37% aqueous formaldehyde (0.06 ml) was added. After standing for 2 h at room temperature, NaCNBH, (65 mg) was added in small portions, and the reaction mixture was left standing overnight. Workup afforded an oily residue that was purified by chromatography on silica gel plates. The oily base (60 mg), eluted with the solvent mixture CHCI,-MeOH-NH,OH (94:5: 1) showed the following properties: [u]D +55" (c CALYCOTOMINE
'Paper no. 60 in the series "Cactus Alkaloids," 'Dedicated to Dr. Peter Kerekes, a Visiting Scientist at the NIH from the Institute oforganic Chemistry, University of Debrecen, Hungary, who died on July 3 1, 1984, from a heart attack. 3Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas 66045.
Jan-Feb 19851
Kerekes eta/.: R-( +)-N-Methylcalycotomine
+
0.4, CHCI,); cims m/z 238 (M+ l), 206 (Mf -CH,OH); 'H nmr (CDCI,) 6.57 (s, l H , ArH), 6.53 (s, l H , A H ) , 3.83 (s, 6H, 2 OCH,), 3.75 (rn, l H , C,-H), 3.52 (rn, 2H, CH,OH), 3.12 (m, 2H, CH,), 2.82 (rn, 2H, CH,), and 2.5 1(s, 3H, NCH,); ir (neat) 3400 (OH) and 1610 (aromatic) cm-'; cd @ (A nm)=-30.28'(283); picrate mp 205" (dec). ACKNOWLEDGMENTS We thank Dr. H. Bruderer from the Research Division of F. Hoffmann-La Roche & Co., AG in Basel for a sample of (+)-calycotomine tartrate and a sample of natural (+)-calycotomine. Support from BMRG 507-RRO-5586 from NIH is acknowledged.
143
LITERATURE CITED 1. 2. 3. 4. 5.
Y.A.H. Mohamed, C.J. Chang, and J.L. McLaughlin,]. Nut. Prod., 42, 197 (1979). A. Brossi, M.F. Rahman, and K.C. Rice, Heterocycles, 7 , 277 (1977). A. Brossi and H. Burkhardt, Helv. Chim. Arta, 44,1558 (1961). K. Takahashi and A. Brossi, Heteracycles, 19, 691 (1983). K. Nakanishi, Plenary lecture at the 14th IUPAC Conference, July 9-14, Poznan, Poland, 1984.
Rereived 30 August 1984
